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Involvement of the Fhit gene in the ionizing radiation-activated ATR/CHK1 pathway

Baocheng Hu1, Shuang-Yin Han, Xiang Wang

  • 1Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Journal of Cellular Physiology
|September 25, 2004
PubMed

Insights

The Fragile Histidine Triad (Fhit) gene is often lost in human cancers. Its absence enhances DNA damage checkpoints via the ATR/CHK1 pathway, promoting cancer cell survival and radioresistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The Fragile Histidine Triad (Fhit) gene is frequently altered in human epithelial tumors, with deletions and reduced expression observed in approximately 70% of cases.
  • While Fhit gene inactivation is linked to tumor progression and Fhit overexpression induces apoptosis, the specific signaling pathways involved remain largely unidentified.

Purpose of the Study:

  • To investigate the role of Fhit gene inactivation in DNA damage response pathways.
  • To determine the impact of Fhit deficiency on cell cycle checkpoints and radioresistance.

Main Methods:

  • Utilized Fhit knockout (Fhit-/-) mouse-derived cells and compared their responses to wild-type counterparts.
  • Analyzed cell cycle checkpoint activation, specifically focusing on the S and G2 phases.
  • Investigated the involvement of the ATR/CHK1 signaling pathway in mediating checkpoint responses.

Main Results:

  • Fhit-/- cells exhibited significantly enhanced S and G2 checkpoint responses compared to wild-type cells.
  • The heightened checkpoint activation in Fhit-/- cells was found to be regulated by the ATR/CHK1 pathway.
  • These enhanced checkpoints contributed to increased radioresistance in Fhit-/- cells, indicating greater survival after DNA damage.

Conclusions:

  • Fhit gene inactivation is associated with augmented DNA damage survival due to overactive ATR/CHK1-regulated checkpoints.
  • The Fhit-dependent DNA damage response pathway may play a crucial role in cancer progression.
  • Targeting the ATR/CHK1 pathway in Fhit-deficient cancers could be a potential therapeutic strategy.

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